PD-1 is recognized as an important player in immune regulation and the maintenance of peripheral tolerance. PD-1 is moderately expressed on naive T, B and NKT cells and up-regulated by T/B cell receptor signaling on lymphocytes, monocytes and myeloid cells (1).
Two known ligands for PD-1, PD-L1 (B7-H1) and PD-L2 (B7-DC) are expressed in human cancers arising in various tissues. In large sample sets of e.g. ovarian, renal, colorectal, pancreatic, liver cancers and melanoma, it was shown that PD-L1 expression correlated with poor prognosis and reduced overall survival irrespective of subsequent treatment (2-13). Similarly, PD-1 expression on tumor infiltrating lymphocytes was found to mark dysfunctional T cells in breast cancer and melanoma (14-15) and to correlate with poor prognosis in renal cancer (16). Thus, it has been proposed that PD-L1 expressing tumor cells interact with PD-1 expressing T cells to attenuate T cell activation and evasion of immune surveillance, thereby contributing to an impaired immune response against the tumor.
Several monoclonal antibodies that inhibit the interaction between PD-1 and one or both of its ligands PD-L1 and PD-L2 are in clinical development for treating cancer.
Anaplastic lymphoma kinase (ALK) is a member of the receptor tyrosine kinase superfamily, and at an amino acid sequence level is most closely related to members such as c-ros oncogene 1 (Ros1), leucocyte tyrosine kinase, the insulin receptor and c-Met (hepatic growth factor receptor) (Kostich M et al, Genome Biology 2002, 3, 1-12). ALK is largely expressed in the developing nervous system (Iwahara T et al, Oncogene 1997, 14, 439-449). Its relative abundance does tend to decrease in the adult animal, though its expression is maintained in certain regions of the brain, spinal cord and the eye (Vernersson et al., Gene Expression Patterns 2006, 6, 448-461).
ALK also has an important role in oncology (Webb T R et al, Expert Reviews in Anticancer Therapy 2009 9 331-355). Point mutations in the full length ALK enzyme that lead to activation of the enzyme, and also increase in expression of the full length enzyme, have both been shown to lead to neuroblastoma (Ogawa S et al., Cancer Sci 2011 102:302-308). In addition, the fusion of ALK with other proteins due to genetic translocation events has also been shown to lead to activated kinase domain associated with cancer. A number of such ALK translocations leading to gene fusions are seen in lymphomas, the most prevalent being the nucleophosmin (NPM)-ALK fusion seen in anaplastic large cell lymphomas (ALCL). ALK fusion with EML4 leads to a chimeric protein (EML4-ALK) responsible for 2-7% of non-small cell lung carcinomas (NSCLC) (Soda M et al, Nature 2007 448 561-567).
ALK inhibitors have been approved for the treatment of ALK-positive metastatic non-small cell lung cancer (NSCLC), and continue to be investigated in the clinical setting.